the two main mechanisms of resistance to amoxicillin/clavulanic acid are: • inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class b, c and d. • alteration of pbps, which reduce the affinity of the antibacterial agent for the target. impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in gram-negative bacteria.
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High doses of amoxicillin, equivalent to those produced by 500- and 750-mg oral doses in humans (area under the plasma concentration-time curve), were effective against a penicillin-resistant strain of Streptococcus pneumoniae in an experimental respiratory tract infection in immunocompromised rats; this superior activity confirms the results of previous studies. An unexpected enhancement of amoxicillin’s antibacterial activity in vivo against penicillin-resistant and -susceptible S. pneumoniae strains was observed when subtherapeutic doses of amoxicillin were coadministered with the β-lactamase inhibitor potassium clavulanate. The reason for this enhancement was unclear since these organisms do not produce β-lactamase. The differential binding of clavulanic acid and amoxicillin to penicillin-binding proteins may have contributed to the observed effects.
Community-acquired respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae (PRSP) are becoming increasingly common worldwide (2, 13, 17), and the ideal therapy remains debatable. Oral amoxicillin and high-dose parenteral benzylpenicillin are effective against infections caused by PRSP (3, 8, 12, 13, 17), and these results have also been demonstrated with experimental models (6, 21).
The combination of amoxicillin and the β-lactamase inhibitor clavulanic acid is frequently used for the treatment of respiratory tract infections (4) and otitis media (7) because of its high level of activity against commonly implicated β-lactamase-producing pathogens, including Haemophilus influenzae and Moraxella catarrhalis (8), and penicillin-susceptible strains of S. pneumoniae. In experimental respiratory tract infections, oral amoxicillin-clavulanic acid demonstrated unexpected activity against strains of S. pneumoniae exhibiting high levels of resistance to penicillin G (22). Amoxicillin-clavulanic acid was also reported to be effective clinically against respiratory tract infections caused by PRSP (19). We therefore undertook further studies to explore the enhanced activities of β-lactam antibiotics observed against penicillin-resistant, β-lactamase-negative pneumococci when these antibiotics are coadministered with clavulanic acid.
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MATERIALS AND METHODS
Bacterial strains.
The MICs for and the sources of the penicillin-resistant clinical isolates of S. pneumoniae, isolates N1387, 11766, and 14319, and a susceptible strain of S. pneumoniae, strain 1629, used in these studies are presented in Table Table1.1. Typically, PRSP strains have altered penicillin-binding proteins (PBPs) with reduced affinities for β-lactams (15). In these studies, S. pneumoniae N1387, the only strain whose PBP profile was characterized, displayed a PBP profile different from that of a typical penicillin-susceptible strain, S. pneumoniae R6, as determined by binding of 3H-benzylpenicillin (8a).
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